期刊
CELL RESEARCH
卷 31, 期 12, 页码 1263-1274出版社
SPRINGERNATURE
DOI: 10.1038/s41422-021-00566-x
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资金
- Sichuan University [20822041D4057]
- Natural Science Foundation of China [82041016, 32070049]
- Ministry of Science and Technology of China [2019YFA0508800]
- Science and Technology department of Sichuan Province [2020YJ0208]
This study presents five cryo-electron microscopy structures of S1PRs bound to diverse drug agonists and the heterotrimeric Gi protein. The structural and functional assays demonstrate the different binding modes of chemically distinct agonists of S1PRs, reveal the mechanical switch that activates these receptors, and provide a framework for understanding ligand selectivity and G protein coupling.
Sphingosine-1-phosphate (S1P) is an important bioactive lipid molecule in cell membrane metabolism and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, physiological homeostasis, and pathogenic processes in various organs. S1PRs are lipid-sensing receptors and are therapeutic targets for drug development, including potential treatment of COVID-19. Herein, we present five cryo-electron microscopy structures of S1PRs bound to diverse drug agonists and the heterotrimeric Gi protein. Our structural and functional assays demonstrate the different binding modes of chemically distinct agonists of S1PRs, reveal the mechanical switch that activates these receptors, and provide a framework for understanding ligand selectivity and G protein coupling.
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